Blood, 1 April 2002, Vol. 99, No. 7, pp. 2283-2284
p21CIP1/WAF1/SDI1 hypermethylation: an
exciting new lead in ALL biology
Roman-Gomez and colleagues (page 2291) have
examined hypermethylation of the p21CIP1/WAF1/SDI1 gene
promoter in bone marrow cells from a large group of children and adult
patients with acute lymphoblastic leukemia (ALL). Hypermethylation, observed in 51 of 124 patients, correlated strongly with decreased p21
mRNA levels and was highly predictive of a poor clinical outcome. Importantly, p21 hypermethylation was a significant independent prognostic factor for disease-free survival in both childhood and adult
ALL. In fact, as a prognostic factor, p21 hypermethylation was fully
comparable to, or even surpassed in predictive power, such
long-established ALL risk factors as age, white blood cell count, or
BCR-ABL expression.
Even though molecular abnormalities involving other cell-cycle
regulatory genes, especially those encoding the INK4 proteins, are commonly encountered in ALL, clear correlations of these
abnormalities with clinical or biologic behavior of the disease have
been elusive. Therefore, the striking effect of p21 methylation status
on the biology of ALL as revealed by Roman-Gomez et al's studies is
quite novel and has major implications for both basic and clinical
research in ALL. First is the possibility that p21 may play a uniquely important role in regulating the proliferation of ALL cells, which consequently may enjoy a growth advantage when p21 expression is
blocked. Second, this consideration should encourage more intensive evaluations of agents that inhibit DNA methylation for the treatment of
ALL. Third, if these observations are confirmed by other studies, p21
methylation status could be used as a stratification tool to provide
effective risk-adapted therapy for ALL, a need that is especially
acute for adults with this disease. Because of the tight correlation
between p21 methylation status and mRNA levels, it is highly plausible
to expect that a simple clinical laboratory test like
immunocytochemistry might one day be used to screen new ALL cases for
p21 expression and to provide meaningful risk stratification.
More work needs to be done: the authors point to the tantalizing
association of coexisting hypermethylation of the p73 gene promoter,
the role of histone deacetylation must be fully explored, and an
alternative mechanism to hypermethylation for p21 silencing remains to
be elucidated. But even with so many unanswered questions, it is
intriguing to consider the many directions this exciting new lead in
ALL biology may eventually take us.
David H. Boldt
University of Texas Health Science Center at San Antonio
